Porcine reproductive and respiratory syndrome virus (PRRSV) is a positive-sense single-stranded RNA virus belonging to the family Arteriviridae. It causes an economically important disease, resulting in an estimated $660 million loss per year to the swine industry in the United States. PRRSV appears to inhibit the synthesis of type I interferons (IFNs) in infected pigs. IFNs are not detectable in the lungs of pigs, in which PRRSV actively replicates. PRRSV-infected pigs develop delayed onset and low titer neutralizing antibodies and weak cell-mediated immune responses. Suppression of innate immunity may be an important contributing factor to PRRSV modulation of host immune responses.
PRRSV can be propagated in vitro in an epithelial-derived monkey kidney cell line, MARC-145, and in primary cultures of porcine pulmonary alveolar macrophages (PAMs). PAMs are the main target cells for PRRSV during its acute infection of pigs. PRRSV infection of PAM and MARC-145 cells in vitro leads to a very low expression of interferon-α (IFN-α) for viral strains studied to date.
Type I IFNs, such as IFN-α and -β, are critical to innate immunity against viral infection and contribute to the modulation of adaptive immunity. The innate immune system is activated after cellular pattern recognition receptors (PRR) sense pathogen associated molecular patterns (PAMPs) of invading pathogens. Host PRRs for RNA viruses include Toll-like receptors (TLRs) and RIG-I-like receptors (RLRs). Activation of the TLR or RLR pathways eventually leads to the secretion of type I IFNs. The binding of type I IFNs to their receptors activates the Janus kinase (JAK)-signal transducer and activator of transcription (STAT) pathway, which induces expression of IFN-stimulated genes (ISGs) and results in the establishment of an antiviral state.
Some PRRSV strains suppress IFN-β expression in MARC-145 cells and PRRSV non-structural proteins (nsp) 1, 2, 4, and 11 inhibit IFN induction when over-expressed. PRRSV can also inhibit IFN downstream signaling and expression of ISGs in both MARC-145 and PAM cells. The nuclear translocation of STAT1/STAT2/IRF9 heterotrimers was blocked in PRRSV-infected cells, while the IFN-induced phosphorylation of STAT1 and STAT2 was not affected.
Many efforts to control PRRS have been attempted, but have been unsuccessful. There is thus an ongoing and long felt need for improved compositions for prophylaxis and/or therapy of PRRS.